Compounds in accordance with the present invention are useful as .beta.-adrenergic blocking agents for the treatment or prophylaxis of cardiac disorders; and for the treatment of glaucoma or lowering of intraocular pressure by topical administration of the compounds to the eye. These compounds have short duration in the systemic circulation, but have good stability in ocular fluid; and thus are particularly useful as glaucoma agents since they have a low potential for producing unwanted systemic side effects.
Glaucoma is a condition of the eye characterized by increased intraocular pressure. Untreated, the condition can eventually lead to irreversible retinal damage and blindness. Conventional therapy for glaucoma has involved topical administration of pilocarpine and/or epinephrine, administered to the eye several times daily.
The use of various .beta.-blocking agents to lower intraocular pressure is well documented. For example, U.S. Pat. No. 4,195,085 to Stone discloses a method for treatment of glaucoma by the optical administration of a .beta.-blocking compound, timolol maleate. U.S. Pat. No. 4,127,674 discloses a method of treating glaucoma with labetalol, a known antagonist of both alpha and beta adrenergic receptors. However, these methods also possess significant drawbacks, in that the absorption of the .beta.-blocking compound into the systemic circulation can cause undesirable side effects. Such side effects result from prolonged .beta.-blocking action on the heart, bronchioles and blood vessels. For example, according to Physicians' Desk Reference, Charles E. Baker, Jr., 35th Edition, 1981, p. 1233, adverse reactions to the topical use of timolol maleate can include bronchospasm and heart failure, as well as cardiac conduction defects. Accordingly, there is a need for a method of treatment for glaucoma or for lowering intraocular pressure which is relatively free of unwanted systemic side effects.
The use of .beta.-blocking agents to lower intraocular pressure can also be accompanied by a local anesthetic activity in the eye which can possibly cause damage to the cornea, and most certainly will cause discomfort to the patient with continued use. There is a need for potent compounds effective in lowering intraocular pressure which have little or no local anesthetic activity in the eye.
The present invention also relates to the treatment or prophylaxis of cardiac disorders. More particularly, the invention relates to a novel method of treatment or prophylaxis of cardiac disorders which comprises administration of .beta.-adrenergic blocking compounds and to compounds useful in such method.
The therapeutic and prophylactic uses of compounds which block sympathetic nervous stimulation of .beta.-adrenergic receptors in the heart, lungs, vascular system and other organs are well documented. Typically, such compounds are administered therapeutically to patients suffering from ischemic heart disease or myocardial infarction for the purpose of reducing heart work, i.e., heart rate and contractile force. Reducing heart work reduces oxygen demand, and may also actually increase oxygen supply. Thus reducing heart work can aid in the prevention of further tissue damage and can relieve angina pectoris.
.beta.-adrenergic stimulation may also aggravate or cause arrhythmias because of increased levels of catecholamines. Thus .beta.-blocking agents may be employed to reduce the risks of arrhythmias.
Heretofore, the emphasis in .beta.-blocker research has been to develop compounds which can be administered to cardiac patients over long periods of time. However, it is often desirable in the critical care setting to quickly reduce heart work or improve rhythmicity during a cardiac crisis, e.g., during or shortly after a myocardial infarction. Conventional .beta.-blocking agents can be employed for such treatment, but their duration of action may be much longer than desired by the physician. A .beta.-blocking agent possessing a long duration of action does not allow precise control of heart work or prompt reversal of the .beta.-blocking effect, which may be required in a critical care setting. For instance, if heart output becomes dangerously low, it is desirable to quickly reduce or eliminate .beta.-blocking activity. The lingering activity of available .beta.-blocking agents can be counterproductive and can greatly complicate the therapeutic decisions required of the physician during such critical care of cardiac patients.
Accordingly there is a need for a pharmaceutical preparation and method of treatment, employing a .beta.-adrenergic blocking compound having a short duration of action in the systemic circulation.